Advances in the Treatment of Psoriasis

Angel S. Pechie, PharmD, RPh; Jennifer L. Hull, PharmD, RPh; and Nancy E. F. Hayden, MA
Published Online: Friday, December 1, 2006

Psoriasis is a chronic, hereditary disease that involves the skin and, in some instances, the joints. Psoriasis affects between 1% and 3% of the population worldwide and nearly 7.5 million individuals in the United States alone.1 The National Psoriasis Foundation estimates that the overall therapy costs for this lifelong disease may exceed $3 billion annually. Quality-of-life studies have defined the impact of psoriasis to be as detrimental to patients as that of cancer, arthritis, or heart disease.2

The immune pathogenesis of psoriasis was identified nearly 20 years ago. Prior to that time, psoriasis was thought to be an epidermal disease resulting from abnormal keratinocyte growth and differentiation. The discovery of psoriasis benefits in a renal transplant patient receiving cyclosporine revolutionized this theory and precipitated the interest in an immunogenic process.3

Psoriasis is a T-cell-mediated disease. Unidentified antigens cause activation of T cells, which then proliferate and enter the systemic circulation. The T cells migrate into the skin and release a number of cytokines (including tumor necrosis factor alpha [TNF-a] and interferon gamma), which cause vascular changes and interfere with normal keratinocyte development.

The diagnosis of psoriasis is typically ascertained by a careful patient history review and a physical examination.4 In rare instances, skin biopsy may be necessary to identify hyperproliferation and inflammation of the epidermis and dermis. Other diseases that can present similarly to psoriasis include tinea corporis and subacute cutaneous lupus erythematosus.

Five types of psoriasis currently are recognized: plaque, guttate, inverse, erythrodermic, and pustular. Plaque psoriasis is the most common form, occurring in >80% of afflicted individuals.5 Two peak ages of onset are recognized: 16 to 22 years and 57 to 60 years.1 Psoriasis is more commonly identified in Caucasian individuals and is more frequent at higher latitudes.5 Prevalence is similar between genders.5 Hereditary factors also influence the disease. Research on the human genome has identified the gene locus, PSORS-1, which is accountable for nearly 50% of the genetic susceptibility to psoriasis.6

Symptoms

Symptoms of psoriasis can vary but most commonly include pruritis, erythema, and possibly pain. In the most common form of the disease, patients are characterized by the development of well-demarcated plaques with silvery scales on the elbows, knees, or scalp. Between 10% and 30% of individuals afflicted with psoriasis will develop psoriatic arthritis, a related condition that causes swelling and tenderness of the joints and is commonly found in the distal extremities.7

In clinical trials, disease severity is assessed by the percentage of body surface involved and the resultant effect on a patient's quality of life, using the Psoriasis Area and Severity Index (PASI) scale. Scores range from 1 to 72, with 72 being the most severe form of the disease. The goal in studies has been to attain a >75% improvement in PASI score in order for a new medication to receive FDA approval.

Conventional Treatment

We will review pharmacotherapy for the most common form of the disease, plaque psoriasis. Patient education is essential to teach avoidance of factors that could cause disease flare-ups (Table 1). Providers need to stress that therapy is meant to control rather than to cure psoriasis. Several organizations have excellent Web-based resources, with information appropriate for both patients and providers (Table 2).

Topical therapy is the mainstay of treatment for patients with localized disease. Adherence to topical regimens can be poor, however. Regular use of emollient agents can help to hydrate and soften the skin. Tar products and anthralin are no longer favored because of their noxious odor and their tendency to cause staining of clothing and skin.

Topical corticosteroids have antiinflammatory and antiproliferative effects and are available in many forms and strengths. Corticosteroids have demonstrated rapid effectiveness and are the most commonly prescribed treatment, despite side effects of cutaneous atrophy, formation of telangiectasia, and hypothalamus-pituitary-adrenal axis suppression.8 Agent selection is based on both the location and the thickness of the plaques. Unfortunately, many patients will experience disease reactivation once corticosteroid treatment is discontinued.

Topical calcipotriene, a vitamin D3 analogue, and tazarotene, a retinoid analogue, inhibit epidermal cell proliferation and enhance normal keratinization. The slow onsets of action and favorable side-effect profiles of these agents are the reasons for their combination with corticosteroid therapy. Their most common side effect is skin irritation, occurring in as many as 25% of patients. Tazarotene should be strictly avoided in pregnant patients because of its teratogenic effects.

Phototherapy and systemic therapies are likely treatment options for patients whose disease is not controlled by topical therapy or whose skin involvement is such that topical therapy is not reasonable (>30% of body surface affected or use of more than 100 g of a steroid preparation per day).1,5,9 In many instances, patients will achieve superior results if phototherapy is combined with topical treatments.Oral retinoid products such as acitretin also can be combined with phototherapy to help reduce the number of treatments necessary to achieve remission.

Phototherapy involves controlled exposure to either ultraviolet B or ultraviolet A (UVA) light. Psoralen, a prescription medication that has photosensitizing properties, is given in combination with UVA exposure. Although both therapies are deemed highly effective, redness or hypopigmentation may occur, and UVA exposure is associated with the development of squamous cell carcinoma.

The use of oral immunosuppressives is limited by their side-effect profiles. Methotrexate inhibits the proliferation of rapidly dividing cells and has a long history of use for psoriasis. It commonly causes nausea and folic acid deficiency and should be used only in patients with adequate renal function. Long-term use is associated with hepatic fibrosis and cirrhosis, particularly in patients using high-dose regimens or concomitant hepatotoxic agents. Bone marrow suppression can occur at any time. Methotrexate is contraindicated in pregnancy.

Cyclosporine decreases the production of inflammatory cytokines, but it is associated with hypertension, nephrotoxicity, and disease relapse after discontinuation. It also is associated with multiple drug interactions, including azole antifungals, nondihydropyridine calcium channel blockers, erythromycin, and statins. Interactions with other agents such as tacrolimus and mycophenolate are still under review.

Biologic Therapy

Biologic therapies for psoriasis that have emerged over the past 5 years represent a promising new area in the treatment of moderate-to-severe psoriasis. These immunosuppressive therapies are designed to target the cells that are responsible in the pathogenesis of the disease, such as T cells and cytokine TNF-a. Inconvenience and dissatisfaction associated with topical and oral therapies have greatly increased patient demand for these injectable products. Multiple randomized clinical trials support the efficacy of biologic therapy in comparison with placebo. No trials have been conducted, however, demonstrating their efficacy in comparison with one another or with other less invasive therapies. Unfortunately, the long-term effectiveness of biologic therapies has yet to be defined.

Alefacept

Alefacept (Amevive) was the first biologic therapy approved for the treatment of moderate-to-severe chronic plaque psoriasis. It inhibits the activation of T cells, while also selectively eliminating memory T cells implicated in psoriasis. Alefacept is administered as a 7.5-mg intravenous (IV) bolus or a 15-mg intramuscular injection at once-weekly office visits for 12 weeks.

Chills have occurred in >5% of patients during IV administration. T-cell counts should be performed weekly to monitor the number of CD4+ T lymphocytes. Therapy may need to be discontinued if the CD4+ count falls below 250 cells/?L during a 1-month period.

A second 12-week course can be given if at least 12 weeks have passed since completion of the first course. Alefacept has reduced disease severity by 75% in up to 40% of patients, with remissions lasting as long as 1 year.2 There are currently no data to support giving more than 2 cycles of alefacept treatment.

Efalizumab

Efalizumab (Raptiva) is an anti-CD11a IgG1 antibody that inhibits the activation and migration of T lymphocytes. In contrast to alefacept, efalizumab should be taken continuously, because the results are reversible on discontinuation. Efalizumab is self-administered as a once-weekly subcutaneous (SC) injection of 1 mg/kg, following a 1-time conditioning dose of 0.7 mg/kg.

Because of the 0.3% incidence of thrombocytopenia observed in a clinical trial, monitoring of platelet counts is recommended. Other side effects include influenza-like symptoms and transient pruritic skin eruptions in previously uninvolved flexural sites. Efalizumab has demonstrated clearing of psoriatic lesions in up to 33% of patients after 12 weeks of therapy. Longterm efficacy data are limited to 27 months.2

Infliximab

Infliximab (Remicade) is approved for chronic-severe plaque psoriasis and psoriatic arthritis. It is an anti-TNF-a chimeric monoclonal antibody that has a long history of success in patients with rheumatoid arthritis and Crohn's disease.

TNF-ais implicated in the pathogenesis of psoriasis by inducing the synthesis of many cytokines, resulting in inflammation and abnormal growth of skin cells. Infliximab has demonstrated skin clearing in up to 90% of plaque psoriasis patients after 10 weeks of therapy.2

The drug is administered as a slow IV infusion of 5 mg/kg over 2 hours. Infusions are repeated at 2 weeks, 6 weeks, and every 8 weeks thereafter. An infusion- related reaction occurs in as many as 20% of patients and is the most common side effect experienced. There is a "black-box" warning regarding the potential risk of infection with the use of infliximab.

It is recommended that patients be given a tuberculin skin test prior to the initiation of drug therapy to rule out latent infection. Infliximab should not be administered to patients with active infections or demyelinating diseases and should be used with caution in patients with congestive heart failure.

Etanercept

The effectiveness of etanercept (Enbrel), another anti-TNF-aantibody, has been demonstrated in psoriatic arthritis and chronic moderate-to-severe plaque psoriasis. Etanercept is self-administered as a once-weekly 50-mg SC injection. Patients using etanercept for plaque psoriasis should initiate it with a 3-month phase in of 50-mg SC twice weekly.

More than 50% of patients have achieved skin clearing of their plaque psoriasis after 12 weeks of treatment. Long-term efficacy has not been established beyond 2 years of therapy.2 Etanercept has a side-effect profile and safety concerns similar to those with infliximab.

Conclusion

Psoriasis is a lifelong disease with a profound burden on the affected individuals. Most patients will require topical therapy in addition to lifestyle modification. Oral immunosuppressives or phototherapies are a more aggressive treatment strategy for the small percentage of patients whose disease is inadequately controlled by topical medications.

Biologic therapy offers a treatment option that targets instigators of disease activity. The high cost of injectible therapy may be offset by decreased overall health care utilization and improvements in quality of life in patients who require this level of management.

Dr. Pechie is a clinical pharmacist with Memorial Hospital of Rhode Island. Dr. Hull is a pharmacist with Stop and Shop Pharmacy. Ms. Hayden is manager of analytical services with Advanced Pharmacy Concepts.

For a list of references, send a stamped, selfaddressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an e-mail request to: arybovic@ascendmedia.com.




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